Kidney cancer (or renal cell carcinoma; RCC) is responsible for 13,000 deaths annually in the US. The disease is frequently asymptomatic, and a third of cases are diagnosed when the disease is already metastatic, at which time it has 95% mortality (Weiss R H, Lin P-Y. Kidney Int 2006; 69(2):224-232). Conventional treatment of RCC has been based on surgical approaches and the administration of the immunomodulating medications interferon and interleukin-2 (reviewed in Weiss R H, Lin P-Y. Kidney Int 2006; 69(2):224-232). These drugs, their combinations with cytotoxic “standard” treatments such as gemcitabine and 5-FU (Stadler W M, Huo D, George C, Yang X, Ryan C W, Karrison T et al. J Urol 2003; 170(4 Pt 1):1141-1145), other cytostatic chemotherapy agents alone and in combination, as well as hormonal manipulation, have all shown no benefit to survival and are thus not generally utilized (reviewed in De Mulder P H, van Herpen C M, Mulders P A. Ann Oncol 2004; 15 Suppl 4:iv319-iv328). Novel targeted therapies are just beginning to emerge, with the most promising being the kinase inhibitors sorafenib and sunitinib (reviewed in Tuma R S. J Natl Cancer Inst 2004; 96(17):1270-1271). However, new pharmacological approaches which would cause standard therapies to be effective in this disease would be a welcome addition to the limited available armamentarium.
p21 is a member of the cip/kip family of cyclin kinase “inhibitors,” but this protein also possesses a variety of properties relating to apoptosis (Matsushita H, Morishita R, Kida I, Aoki M, Hayashi S, Tomita N et al. Hypertension 1998; 31:493-498; Asada M, Yamada T, Ichijo H, Delia D, Miyazono K, Fukumuro K et al. EMBO J 1999; 18(5):1223-1234; Tian H, Wittmack E K, Jorgensen T J. Cancer Res 2000 Feb. 1; 60 (3):679-84 2000: 60:679-684; Fan Y, Borowsky A D, Weiss R H. Mol Cancer Ther 2003; 2(8):773-782) as well as cell proliferation (Weiss R H, Joo A. Randour C. J Biol Chem 2000; 275:10285-10290; Kavurma M K, Khachigian L M. J Biol Chem 2003: 278:32537-32543; Dong Y. Chi S L, Borowsky A D, Fan Y, Weiss R H. Cell Signal 2003; 16(2):263-269). The initial descriptions of p21 focused on its location in the tumor suppressor pathway downstream of p53 (el-Deiry W S, Tokino T, Velculescu V E, Levy D B, Parsons R Trent J M et al. Cell 1993; 75:817-825), its function as an inhibitor of G1 cyclin kinases (Xiong Y, Hannon G J, Zhang H, Casso D, Kobayashi R, Beach D. Nature 1993; 366(6456):701-704; Harper J W, Adami G R, Wei N, Keyomarsi K, Elledge S J. Cell 1993; 75(4):805-816), and its role in differentiation (Sherr C J, Roberts J M. Genes and Dev 1999; 13:1501-1512). However, more recent investigations have shown that p21 also plays roles in allowing cell cycle transit as well as preventing apoptosis (Fan Y P, Weiss R H. J Am Soc Nephrol 2004; 15(3):575-584; Liu X F, Xia Y F, Li M Z, Wang H M, He Y X, Zheng M L et al. Cell Biol Int 2006; 30(3):283-287; Sohn D, Essmann F, Schulze-Osthoff K, Janicke R U. Cancer Res 2006: 66(23):11254-11262; Park S H, Park J Y, Weiss R H. J Urol 2008; 180(1):352-360); since programmed cell death is the ultimate mechanism by which cancer chemotherapeutics exert their salutary effects on tumor cells, this property of p21 has considerable untapped potential to be of fundamental importance in the therapy of human cancer.
For many cancers, treatment with DNA damaging agents, at doses required for efficacy, are associated with unacceptable adverse effects as well as inadequate cure rates. Kidney cancer is notoriously chemotherapy as well as “conventional” immunotherapy resistant, although recent work with kinase inhibitors has shown promise for late-stage disease. A possible reason for chemotherapy resistance is failure of these agents, when used alone, to cause cancer cell apoptosis, since inactivation of apoptosis is essential for cancer development (Brown J M, Attardi L D. Nat Rev Cancer 2005; 5(3):231-237; Evan G I, Vousden K H. Nature 2001; 411 (6835):342-348).
In breast cancer, increased cytosolic p21 or higher (total) p21 expression by immunostaining have been linked to poorer prognosis (Winters Z E, Leek R D. Bradburn M J, Norbury C J, Harris A L. Breast Cancer Res 2003; 5(6):242-249), and efforts to attenuate p21 in vitro in breast cancer, and in vivo in breast, colon and esophageal cancers, have led to salutary effects on tumors cells. In kidney cancer, p21 has been shown to have prognostic value in the clear cell variety which is a function of whether patients have localized or metastatic disease at diagnosis (Weiss R H, Borowsky A D, Seligson D, Lin P Y. Dillard-Telm L, Belldegrun A S et al. J Urol 2007; 177(1):63-68). The likelihood that p21 is preventing cells from undergoing apoptosis and thereby allowing their escape from chemotherapy is supported by the finding that antisense oligodeoxynucleotides in vitro cause kidney cancer cells to be sensitized to DNA-damaging therapy, consistent with the anti-apoptotic effect of p21 observed in other cell lines (Asada M. Yamada T, Ichijo H, Delia D, Miyazono K. Fukumuro K et al. EMBO J 1999; 18(5):1223-1234).
p21 inhibitors have been reported previously (WO 10/039668), and sorafenib has been reported as a potent and stable p21 inhibitor (Inoue et al. (2011) Cancer Biol. Ther. 12(9):827-836). However, there still exists a need for compounds possessing similar or increased activity, with improved kinase selectivity. Surprisingly, the present invention provides compounds and compositions that meet this and other needs.